Presentation Authors: Tariq A. Khemees*, Bing Yang, Adam Schultz, Tyler Etheridge, Glen Leverson, Madison, WI, Geoffrey Sonn, Palo Alto, CA, Cristina Magi-Galluzzi, Erick A. Klein, Cleveland, OH, Michael J. Fumo, Rockford, IL, David F. Jarrard, Madison, WI
Introduction: Prostate cancer (PC) is typically found in multifocal locations within the prostate raising the possibility of molecular field defect in histologically normal prostate tissue. Epigenetic alterations including DNA methylation are increasingly implemented in risk assessment, cancer diagnosis and therapy monitoring. Our goal was to compare variations in DNA methylation at multiple loci across histologically normal biopsies from men with and without PC.
Methods: Four centers contributed archived cancer-negative prostate biopsy tissue blocks from 129 patients. The non-tumor associated (NTA) controls were from patients who underwent 2 or more negative biopsies within 24 months. Tumor associated (TA) benign biopsies were from patients who were diagnosed with PC and underwent prostatectomy to confirm a final Gleason score of â‰¥7. After central re-review of slides, biopsy tissue was analyzed for DNA methylation using pyrosequencing, encompassing CpG sites across 6 genes. Predictive accuracy for PC detection was measured using ROC. The correlation of methylation for each CpG site in two biopsy samples was calculated for the entire cohort. Methylation variation was further elucidated in a subset of patients with four biopsy samples.
Results: Patients diagnosed with GS â‰¥7 PC (TA, N=77) and the control group (NTA, N=52) demonstrate robust methylation differences across all CpG sites (p < 0.05) at CpG shores near CAV1, EVX1, FGF1, NCR2, PLA2G16 and SPAG4. The CpG sites with the highest AUC value from each gene locus was selected for a comparison of methylation variation. Five of the six genes demonstrate higher correlation values in NTA than TA biopsies (p < 0.05). Analyzing samples with 4 biopsies revealed this increase in methylation variation in TA biopsies across prostate regions from 5 of the above loci (Figure).
Conclusions: The methylation status of CAV1, EVX1, FGF1, NCR2, PLA2G16 and SPAG4 differ between TA and NTA normal prostate tissues marking a field of epigenetic susceptibility associated with the development of PC. That methylation is variable between biopsies across a single gland provides clues to the biology of multifocal PC development and could potentially be used to improve biomarker detection.
Source of Funding: Funded by Urology Care Foundation/ AUA Research Scholar Award (T.K.)